The present invention relates to 4-halogenated steroid compounds, their preparation process, their use as medicaments and the pharmaceutical compositions containing them.
Osteoporosis is a pathology which is characterized by a quantitative and qualitative reduction in bone matter, sufficient to lead to vertebral or peripheral fractures, in a spontaneous fashion or on occasions due to minimal traumas. Although this illness has many factors at its origin, it is the menopause which in women constitutes the dominating factor in bone loss or osteopenia.
This osteopenia manifests itself by a rarefaction and modification of the architecture of the spongy bone, the consequence of which is to increase the fragility of the skeleton and the risk of fractures. Bone loss increases strongly after the menopause due to the suppression of ovarian function and reaches 3 to 5% per year before slowing down after 65 years old.
For a therapeutic purpose, the post-menopause hormonal deficiency can be compensated for by a hormone replacement therapy where oestrogen plays a major role in preserving the bone mass. Jin et al (Steroids, Vol. 60 (1995) pp. 515-518 and Anstead et al (Steroids, Vol. 62 (1996) pp. 268-303) describe estradiol derivatives showing affinity to the estradiol receptor. But long-term oestrogenotherapy is sometimes accompanied by undesirable effects on the genital apparatus (endometrial hyperplasia, breast tumors . . . ), which constitutes a major drawback and limits its use.
It is therefore convenient to find compounds other than oestradiol having a dissociated oestrogen activity, namely an oestrogen activity at the bone level, while having no or little endometrial hyperplasia activity, nor breast tumor proliferation activity.
Therefore, a subject of the invention is the compounds of general formula (I): 
in which:
R1 represents a hydrogen atom, a (CH2)mxe2x80x94Ar, (CO)xe2x80x94Ar, (CH2)mxe2x80x94Alk or (CO)xe2x80x94Alk radical,
R2 represents a radical derived from a linear or branched, saturated or unsaturated hydrocarbon containing 1 to 6 carbon atoms
D represents the remainder of a pentagonal or hexagonal ring optionally substituted and optionally carrying an unsaturation,
X represents a halogen atom,
Y is chosen from O, S, SO, SO2 and NH,
n is an integer varying from 2 to 8,
either R3 and R4, identical or different, represent a hydrogen atom, a (CH2)mxe2x80x94Ar, (CH2)mxe2x80x94Het or (CH2)mAlk group,
or R3 and R4 form together with the atom of nitrogen to which they are linked an aromatic or non-aromatic, saturated or unsaturated mono- or polycyclic heterocycle with 3 to 15 members optionally containing 1 to 3 additional heteroatoms chosen from oxygen, sulphur and nitrogen, non-substituted or substituted,
Ar representing a carbocyclic aryl group containing 6 to 18 carbon atoms, Het representing a radical derived from a saturated or unsaturated aromatic or non-aromatic heterocycle containing 1 to 9 carbon atoms and 1 to 5 heteroatoms chosen from oxygen, nitrogen or sulphur atoms, Alk representing a radical derived from a saturated or unsaturated, linear, branched or cyclic, non-aromatic hydrocarbon and containing 1 to 12 carbon atoms, the Ar, Het or Alk radicals being able to be substituted or non-substituted, m represents 0, 1, 2 or 3, as well as their addition salts with bases or acids.
By halogen is meant: iodine, bromine, chlorine or fluorine.
By (CH2)m is meant the following values: single bond in the case where m is equal to 0, CH2, (CH2)2 and (CH2)3.
By the term Ar representing the carbocyclic aryl group containing 6 to 18 carbon atoms, is meant a derivative of an aromatic cyclic hydrocarbon such as the phenyl, naphthyl, phenanthrenyl radical or a derivative of a condensed, bicyclic or tricyclic hydrocarbon containing a benzene ring such as indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl. The junction is carried out at the level of the benzene ring. Preferably it is phenyl.
By the term (Het) representing a radical derived from a saturated or unsaturated, aromatic or non aromatic heterocycle containing 1 to 9 carbon atoms and 1 to 5 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, the following are designated in particular:
heterocyclic monocyclic radicals, for example thienyl, furyl, pyrannyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radicals,
condensed heterocyclic rings, for example benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or also condensed polycyclic systems constituted by heterocyclic moncyclics as defined above such as for example furo[2,3-b]pyrrole or thieno[2,3-b]furan,
or saturated heterocycles such as pyrrolidine, piperidine, morpholine.
By the term (Alk) representing a radical derived from a saturated or unsaturated, linear, branched or cyclic non-aromatic hydrocarbon, is designated in the case of acyclic hydrocarbons the alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl 3-methyl-3ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, the alkenyl radicals such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or the alkynyl radicals such as ethynyl, propynyl, propargyl, butynyl or isobutynyl, and in the case of cyclic radicals, the cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
It will preferably be methyl and ethyl radicals. By COxe2x80x94Alk is preferably meant COCH3 and COET, by COxe2x80x94Ar is preferably meant the benzoyl radical, when m is different from zero, (CH2)mxe2x80x94Ar will preferably be the benzyl group.
When R3 and R4 form together with the nitrogen atom to which they are linked a heterocycle, it is in particular mono- or bicyclic heterocycles optionally containing another heteroatom chosen from oxygen and nitrogen such as the following unsaturated heterocycles: pyrrolyl, imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazolinyl, pyrazolinyl, thiazolinyl, or, more particularly, the following saturated heterocycles: 
When the different Alk, Ar, Het groups, as well as the remainder of a pentagonal or hexagonal ring mentioned above, are substituted, they can in particular be substituted by the following radicals:
halogen, namely fluorine, chlorine, bromine or iodine, alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, amino, alkylamino such as methylamino or ethylamino, dialkylamino such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals being optionally in oxidized form, aminoalkyl such as aminomethyl or aminoethyl, dialkylaminoalkyl such as dimethylamino methyl or ethyl, dialkylaminoalkyloxy such as dimethylamino ethyloxy, hydroxyl optionally acylated, acyl such as acetyl, propionyl, butyryl, benzoyl, free, esterified carboxy such as alkoxy carbonyl for example methoxy carbonyl or ethoxy carbonyl, cyano, trifluoromethyl, aryl such as phenyl, aralkyl such as benzyl, alkyl, alkenyl or alkynyl these radicals being themselves optionally substituted by the halogen, alkyl, alkoxy, alkylthio, aminoalkyl or dialkylamino radicals indicated above.
Of course, the expression xe2x80x9csubstitutedxe2x80x9d indicates that one or more identical or different substituents can be present. In the case of (Het), the substituents can be at the level of the NH or carbon atom.
Of course the values of R1, R2, R3 and R4, are independent of each other.
The invention naturally extends to the salts of the compounds of formula (I), such as for example the salts formed with mineral or organic acids on the amine. It can then be one of the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulphonics such as methane or ethane sulphonics, arylsulphonics, such as benzene or paratoluene sulphonics and arylcarboxylics. When the compounds of formula (I) contain an acid function, the invention extends to the salts of alkali metals, alkaline earth or ammonium, optionally substituted.
A more particular subject of the invention is the compounds of general formula (I) as defined above in which (D) represents the remainder of a pentagonal ring of formula: 
in which
R2 retains the same meaning as previously, either R5 represents an OH, Oxe2x80x94(CH2)mxe2x80x94Alk, Oxe2x80x94(CO)xe2x80x94Alk, Oxe2x80x94(CH2)mxe2x80x94Ar, Oxe2x80x94(CO)xe2x80x94Ar, Oxe2x80x94(CH2)mxe2x80x94Het, Oxe2x80x94(CO)xe2x80x94Het radical and
R6 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing 1 to 6 carbon atoms substituted or non substituted, m, Alk, Ar and Het being as defined previously,
or R5 and R6 form together with the carbon atom which carries them one of the following rings: 
in which
z represents a xe2x80x94(CH2)1xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)1xe2x80x2 group; 1 being an integer comprised between 1 and 4 and 1xe2x80x2 being an integer equal to 1 or 2,
or R5 and R6 form together an oxo group or NOH, as well as their addition salts with acids or bases.
A quite particular subject of the invention is the compounds of formula (I) as defined previously corresponding to general formula (Ixe2x80x2): 
in which:
Xxe2x80x2 represents a chlorine or bromine atom
nxe2x80x2 is comprised between 2 and 5, either Rxe2x80x23 and Rxe2x80x24, identical or different, represent an alkyl radical containing 1 to 6 carbon atoms
or Rxe2x80x23 and Rxe2x80x24 form together with the nitrogen atom to which they are linked, a saturated mono- or polycyclic remainder with 3 to 15 members optionally containing an additional heteroatom chosen from oxygen, sulphur and nitrogen,
Rxe2x80x25 and Rxe2x80x26 have the same meaning as R5 and R6, as well as their addition salts with acids and bases.
A quite particular subject of the invention is the compounds of formula (I) as defined previously corresponding to general formula (Ixe2x80x2) in which:
either Rxe2x80x25 represents an OH radical and Rxe2x80x26 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing 1 to 6 carbon atoms, substituted or non-substituted,
or Rxe2x80x25 and Rxe2x80x26 form together with the carbon atom that carries them one of the following rings: 
or Rxe2x80x25 and Rxe2x80x26 form together an oxo group, as well as their addition salts with acids or bases.
A quite particular subject of the invention is the, compounds of formula (I) corresponding to general formula (Ixe2x80x2) as defined previously in which:
Xxe2x80x2 represents a chlorine atom
nxe2x80x2 is equal to 2,
either Rxe2x80x23 and Rxe2x80x24, identical or different, represent an alkyl radical containing 1 to 6 carbon atoms
or Rxe2x80x23 and Rxe2x80x24 form together with the nitrogen atom the following saturated heterocycles: 
and either Rxe2x80x25 represents an OH radical and Rxe2x80x26 represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing 1 to 6 carbon atoms, substituted or non substituted,
or Rxe2x80x25 and Rxe2x80x26 form together with the carbon atom which carries them one of the following rings: 
or Rxe2x80x25 and Rxe2x80x26 form together an oxo group, as well as their addition salts with acids or bases.
A quite particular subject of the invention is the compounds of formula (I) as well as their addition salts with acids the names of which follow:
4-chloro-3-hydroxy-11xcex2-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one,
4-chloro-3-hydroxy-11xcex2-[4-[2-(dimethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one,
4-chloro-3-hydroxy-11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one,
4-chloro-3-hydroxy-11xcex2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one,
4-bromo-3-hydroxy-11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-17-one,
4-chloro-11xcex2-[4-[2-(dimethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11xcex2-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-bromo-11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11xcex2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11xcex2[-4-[2-(diethylamino)ethoxy]phenyl]-19-nor-17alpha-pregna-1,3,5(10)-triene-20-yne-3,17beta-diol,
4-chloro-11xcex2-[4-[3-(1-piperidinyl)propoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11xcex2-[4-[4-(1-piperidinyl)butoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11xcex2-[4-[5-(1-piperidinyl)pentyloxy]phenyl]-estra-1,3,5 (10)-triene-3,17beta-diol,
gamma lactone of (17alpha)-4-chloro-3,17beta-dihydroxy-11xcex2-[(4-[2-(diethylamino)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carbdxylic acid,
gamma lactone of (17alpha)-4-chloro-3,17beta-dihydroxy-11xcex2
[4-[2-(1-pyrrolindinyl)ethoxy)phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid,
gamma lactone of (17alpha)-4-chloro-3,17beta-dihydroxy-11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid,
gamma lactone of (17alpha)-4-chloro-3,17beta-dihydroxy-11xcex2-[4-[3-(1-piperldinyl)propoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid,
gamma lactone of (17alpha)-4-chloro-3,17beta-dihydroxy-11xcex2-[4-[4-(1-piperidinyl)butoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid,
gamma lactone of (17alpha)-4-chloro-3,17beta-dihydroxy-11xcex2-[4-[5-(1-piperidinyl)pentyloxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid,
(17beta)-4-chloro-11xcex2-[4-[2-(diethylamino)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2xe2x80x2(5xe2x80x2H)furan]-3-ol,
(17beta)-4-chloro-11-[4-[2-(1-piperidinyl)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2xe2x80x2(5xe2x80x2H)furan]-3-ol,
(17beta)-4-chloro-11xcex2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2xe2x80x2(5xe2x80x2H)furan]-3-ol,
(17beta)-4-chloro-4xe2x80x2,5xe2x80x2-dihydro-11xcex2-[4-[2-(1-piperidinyl) ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2xe2x80x2(3xe2x80x2H)furan]-3-ol,
(17beta)-4-chloro-11xcex2-[4-[3-(1-piperidinyl)propoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2xe2x80x2(5xe2x80x2H)furan]-3-ol,
(17beta)-4-chloro-4xe2x80x2,5xe2x80x2-dihydro-11xcex2-[4-[3-(1-piperidinyl)propoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2xe2x80x2(3xe2x80x2H) furan]-3-ol,
(17beta)-4-chloro-11xcex2-[4-[4-(1-piperidinyl)butoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2xe2x80x2(5xe2x80x2H)furan]-3-ol,
(17beta)-4-chloro-4xe2x80x2,5xe2x80x2-dihydro-11xcex2-[4-[4-(1-piperidinyl)-butoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2xe2x80x2(3xe2x80x2H)furan]-3-ol,
4-chloro-11xcex2-[4-[2-(diethylamino)ethoxy]phenyl]-17alpha-methyl-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-17alpha-methyl-11xcex2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
Quite particularly a subject of the invention is also the compound of formula (I) as defined above, the name of which follows:
4-chloro-11xcex2-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol, as well as its addition salts with acids.
A subject of the invention is also a preparation process for the compounds of general formula (I) as defined previously, characterized in that a compound of general formula (II): 
in which D and R2 are as defined previously, R7 represents one of the following groups: 
in which n, Y, R3 and R4 are as defined previously, P is a protective group, Hal represents a halogen,
is subjected to the action of a halogenation reagent in order to obtain the compound of formula (III): 
which is subjected to the action of an aromatization reagent of ring A, then to the action of a base in order to obtain the compound of formula (IV) corresponding to certain compounds of general formula (I): 
which compounds of formula (II), (III) or (IV) are subjected, if desired and if necessary, in an appropriate order, to one or more of the following reactions:
protection of the compounds in which R7 is a xe2x80x94Phxe2x80x94YH group,
deprotection of the compounds in which R7 is a Phxe2x80x94YP group,
the action of a compound of formula Hal1xe2x80x94(CH2)nxe2x80x94Hal2 on the compounds in which R7 is a xe2x80x94Phxe2x80x94YH group, Hal1 or Hal2 identical or diffe rent representing a halogen in order to obtain compounds in which R7 is a xe2x80x94Phxe2x80x94Yxe2x80x94(CH2)nxe2x80x94Hal2 group,
the action of a compound of formula R3xe2x80x94NHxe2x80x94R4 on the compounds in which R7 is a Phxe2x80x94Yxe2x80x94(CH2)nxe2x80x94Hal2 group, in order to obtain compounds in which R7 is a Phxe2x80x94Yxe2x80x94(CH2)nxe2x80x94NR3R4 group,
the action of a halide salt (Mxe2x80x94Hal3) on the compounds in which R7 is a Phxe2x80x94Yxe2x80x94(CH2)nxe2x80x94Hal2 group in order to obtain the compounds in which R7 is a xe2x80x94Phxe2x80x94Yxe2x80x94(CH2)nxe2x80x94Hal3 group,
protection of the OH group in position 3 or 17,
deprotection of the OH group in position 3 or 17,
alkylation of the OH group in position 3 or 17,
acylation of the OH group in position 3 or 17,
the action of a reducing agent when D represents the remainder of a pentagonal ring as defined previously and R5 and R6 together form an oxo group,
the action of an organometallic on the compounds of formula (IV) with D representing the remainder of a pentagonal ring as defined previously and R5 and R6 together forming an oxo group,
the action of a lactonization agent on the compounds of formula (IV) with D representing the remainder of a pentagonal ring as defined previously and R5 and R6 forming together an oxo group,
the action of a reducing agent of the double bond, when D represents the remainder of a pentagonal ring as defined previously and R5 and R6 form together with the carbon that carries them, an Oxe2x80x94(CH2)nxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94 group,
the action of a reducing agent of the double bond, when D represents the remainder of a pentagonal ring as defined previously, and R6 is an alkenyl or alkynyl radical containing 2 to 6 carbon atoms,
halogenation in position 4, then aromatization of ring A, of the compound of general formula (II),
aromatization of ring A of the compound of formula (III),
salification.
The action of a halogenation reagent such as N-bromosuccinimide or N-chlorosuccinimide on the compounds of formula (II) is carried out in particular in the presence of a dipolar aprotic solvent such as dimethylformamide.
The aromatization reaction followed by the saponification reaction (action of the base) is carried out according to standard methods as described in the European Patent 0097572. A mixture of acetic anhydride and acetyl bromide is preferably used as the aromatization agent then a base such as soda in methanol as the saponification agent.
The protection and deprotection reactions are standard methods known to a person skilled in the art. A fairly. complete review is found in the following work: Protective groups in organic synthesis T. W Greene, John Wiley and Sons (1981).
The protective group P preferably represents an alkyl radical containing 1 to 4 carbon atoms, a benzyl group, an RCRDRESi group, in which RC, RD and RE, identical or different, independently of each other each represent an alkyl radical containing 1 to 4 carbon atoms or a phenyl group. Quite particularly it is the Si(Me)2CMe3 or xe2x80x94Si(Ph)2CMe3 groups.
As an example, the deprotection reactions of the compounds of formula (II), (III) or (IV) with R7=Phxe2x80x94OP or the compounds of formula (IV) the 3-OH of which is protected (3-OP), when P is a methyl radical, can be carried out by the action of tribromobdrane in dichloromethane or hydrochloric acid in pyridine, the deprotection reactions when P is a benzyl group can be carried out by the action of hydrogen in the presence of palladium on carbon in ethyl acetate or by the action of trifluoroacetic acid, the deprotection reactions when P is a tertbutyldiphenylsilyl group can be carried out by the action of tetrabutyl ammonium fluoride in solution in tetrahydrofuran.
When P is a tetrahydropyrannyl group, the deprotection is carried out in the presence of an aqueous acid in an alcoholic solvent and preferably by the action of hydrochloric acid in methanol.
The action of a compound of formula Hal1xe2x80x94(CH2)nxe2x80x94Hal2 on a compound of formula (II), (III) or (IV) in which R7=Phxe2x80x94YH can be carried out, in particular when Y=O, in the presence of a base in a solvent such as acetone.
The action of a compound of formula R3xe2x80x94NHxe2x80x94R4 on the compounds in which R7 is a Phxe2x80x94Yxe2x80x94(CH2)nxe2x80x94Hal2 group is carried. out under standard conditions for the substitution of nucleophiles, in particular in the presence of an aprotic solvent such as tetrahydrofuran.
The substitution reaction of a halogen by another when in particular R7 is a Phxe2x80x94Yxe2x80x94(CH2)nxe2x80x94Cl group is preferably carried out by the action of NaI in methyl-ethylketone.
The alkylation or acylation reactions of the OH group in position 3 or 17 are carried out by standard methods known to a person skilled in the art.
The reduction of 17-keto into the corresponding alcohol (R5=OH and R6=H) is carried out according to standard methods, in particular by the action of an alkaline borohydride such as sodium borohydride in methanol or ethanol or by the action of aluminium and lithium tetrahydride.
The action of an organometallic on 17-keto allows access to the products of formula (IV) in which D represents the remainder of a pentagonal ring as defined previously, R5 is a hydroxyl and R6 represents an optionally substituted alkyl, alkenyl, alkynyl radical.
The organometallic derivative of an alkyl, alkenyl or alkynyl is chosen from the magnesium compounds of formula AlkMgHal and the lithium compounds of formula AlkLi in which Alk represents an alkyl, alkenyl or alkynyl group containing at most 8 carbon atoms, Hal represents a halogen atom. In a preferred method of implementing the process, Hal represents a chlorine, bromine or iodine atom, preferably bromine. The reaction preferably takes place in the presence of cerium chloride. In a preferred method for implementing the process, Hal represents a chlorine, bromine or iodine atom, preferably bromine. The lactonization reaction from 17 keto is carried out according to the method of STURTZ (ref: G. STURTZ and J-J. YAOUANC, Synthesis, (1980), 289) in particular in the presence of alkyl bisdimethylamidophosphate in the presence of an alkyllithium compound such as n-butyllithium in tetrahydrofuran.
The total or partial reduction reaction when R6 is an alkenyl or alkynyl or when R5 and R6 form together with the carbon that carried them an Oxe2x80x94(CH2)mxe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94 group, can be carried out either in a total manner by the action of hydrogen in the presence of a catalyst such as palladium on carbon or a rhodium catalyst such as Wilkinson""s reagent or in a partial manner (alkynyl becomes alkenyl) by the action of a poisoned catalyst such as palladium on barium sulphate poisoned with pyridine or triethylamine.
The esterification and salification reactions are carried out by current methods known to a person skilled in the art.
A more particular subject of the invention is a preparation process for the compounds of general formula (Ixe2x80x2) as described previously characterized in that a compound of general formula compound (IIxe2x80x2): 
in which Rxe2x80x25 and Rxe2x80x26 are as defined previously, Rxe2x80x27 represents: 
is subjected to the action of a halogenation reagent in order to obtain the compound of formula (IIIxe2x80x2): 
which is subjected to the action of an aromatization reagent of ring A, then to the action of a base in order to obtain the compound of formula (IVxe2x80x2) corresponding to certain compounds of general formula (Ixe2x80x2): 
which compounds of formula (IIxe2x80x2), (IIIxe2x80x2) or (IVxe2x80x2), are subjected, if desired and if necessary, in an appropriate order, to one or more of the following reactions:
protection of the compounds in which Rxe2x80x27 is a xe2x80x94Phxe2x80x94OH group,
deprotection of the compounds in which Rxe2x80x27 is a Phxe2x80x94OP group,
the action of a compound of formula Hal1xe2x80x94(CH2)nxe2x80x94Hal2 on the compounds in which Rxe2x80x27 is a xe2x80x94Phxe2x80x94OH group, Hal1 or Hal2, identical or different, representing a halogen in order to obtain the compounds in which R7 is a xe2x80x94Phxe2x80x94Oxe2x80x94(CH2)nxe2x80x94Hal2 group,
the action of a compound of formula Rxe2x80x23xe2x80x94NHxe2x80x94Rxe2x80x24 on the compounds in which Rxe2x80x27 is a Phxe2x80x94Oxe2x80x94(CH2)nxe2x80x94Hal2 group, in order to obtain the compounds in which Rxe2x80x27 is a Phxe2x80x94Oxe2x80x94(CH2)nxe2x80x94NRxe2x80x23Rxe2x80x24 group,
the action of a halide salt (Mxe2x80x94Hal3) on compounds in which Rxe2x80x27 is a Phxe2x80x94Oxe2x80x94(CH2)nxe2x80x94Hal2 group in order to obtain the compounds in which R7 is a xe2x80x94Phxe2x80x94Oxe2x80x94(CH2)nxe2x80x94Hal3 group,
protection of the OH group in position 3 or 17,
deprotection of the OH group in position 3 or 17,
alkylation of the OH group in position 17,
acylation of the OH group in position 17,
the action of a reducing agent when Rxe2x80x25 and Rxe2x80x26 together form an oxo group,
the action of an organometallic on the compounds of formula (IVxe2x80x2) with Rxe2x80x25 and Rxe2x80x26 together forming an oxo group,
the action of a lactonization agent on the compounds of formula (IVxe2x80x2) with Rxe2x80x25 and Rxe2x80x26 together forming an oxo group,
the action of a reducing agent of the double bond, when Rxe2x80x25 and Rxe2x80x26 form together with the carbon which carries them, an Oxe2x80x94(CH2)1xe2x80x2xe2x80x94CHxe2x95x90CHxe2x80x94 group,
the action of a reducing agent of the double bond, when Rxe2x80x26 is an alkenyl or alkynyl radical containing 2 to 6 carbon atoms,
halogenation in position 4, then aromatization of ring A, of the compound of formula (IIxe2x80x2),
aromatization of the compound of formula (IIIxe2x80x2),
salification.
The compounds of general formula (I) as well as their addition salts with pharmaceutically acceptable acids have oestrogen, anti-oestrogen and anti-proliferative activities.
Therefore the compounds of formula (I) can be used in the treatment of disorders linked to hypofolliculinia, for example, amenorrheas, dysmenorrheas, repeated abortions, premenstrual disorders, in the treatment of certain oestrogen-dependent pathologies such as prostatic adenomas or carcinomas, mammary carcinomas and their metastases or in the treatment of benign breast tumors, as an anti-uterotrophic as well as in the replacement treatment for the menopause or the perimenopause.
Among the symptoms and consequences linked to the menopause are more specifically meant hot flushes, sweats, vaginal atrophy and dryness, urinary symptoms and in the long term a reduction in bone mass and an increased risk of fractures, and the loss of the cardiovascular protection provided by the oestrogens.
In particular, the compounds of formula (I) and their addition salts with pharmaceutically acceptable acids or bases can be used in the prevention or the treatment of osteoporosis.
The compounds of formula (I) and their addition salts with pharmaceutically acceptable acids can also be used for the prevention or the treatment of osteoporosis in man.
They can also be used for the prevention or the treatment of secondary osteoporoses (for example cortisonal, linked with immobilization).
The compounds of formula (I) and their addition salts with pharmaceutically acceptable acids or bases in particular have a dissociated oestrogenic activity.
By dissociated oestrogenic activity is meant an oestrogenic activity at bone level while demonstrating only minimal activity at uterine level, thus not entailing an endometrial proliferation (much lower activity than that of oestradiol).
Furthermore, the compounds according to the invention have the following advantages:
They have an anti-oestrogenic activity at the level of the breast. Unlike oestradiol, they do not stimulate the growth of human mammary tumor cells and can even inhibit their growth. The compounds according to the invention are therefore particularly advantageous for the treatment of the menopause in women at risk from breast cancer (family antecedents) who are therefore excluded from a replacement treatment using oestradiol.
They can also be used in the treatment of breast cancers.
They lead to a lowering of the seric cholesterol level to a level equivalent to that induced by oestradiol. Therefore, they strengthen cardiovascular protection.
Finally, as the compounds according to the invention have no oestrogen activity at the uterine level, they do not require to be administered in combination with a progestomimetic compound.
A subject of the invention is thus compounds of general formula (I) as well as their addition salts with pharmaceutically acceptable acids or bases, as medicaments.
A more particular subject of the invention is compounds of formula (I) and their addition salts with pharmaceutically acceptable acids or bases as medicaments used for the prevention or the treatment of osteoporosis.
The invention extends to the pharmaceutical compositions containing at least one of the medicaments defined above as active ingredient.
The compounds of formula (I) are used by digestive, parenteral or local route, for exemple by percutaneous route. They may be prescribed in the form of plain or coated tablets, capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, microspheres, implants, intravaginal rings, patches, which are prepared according to the usual methods.
The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
The useful dose varies as a function of the illness to be treated and the administration route; it can vary for example from 1 to 1000 mg per day for an adult by oral route. Patent 0057115.
The compounds of general formula (II) or (IIxe2x80x2) with 
can also be formed from the compounds of formula (IIa): 
in which D, R2, Rxe2x80x25 and Rxe2x80x26 are as defined previously and K represents a protective group of the ketone function,
which is subjected to the action of an O-alkylation reagent of formula Halxe2x80x94(CH2)nxe2x80x94Hal then to the action of a dehydration reagent which is equally capable of releasing the ketone.
The compounds of formula (IIa) or (IIxe2x80x2a) are also known compounds and described in the following patent:
U.S. Pat. No. 5,043,332.
A subject of the invention is also, as intermediate products, the compounds of formulae (III), (IIIxe2x80x2), (IV) and (Ivxe2x80x2).
The examples below illustrate the invention without however limiting it.
Solvents described in the examples: AcOEt (ethyl acetate), TEA (triethylamine), CH2Cl2 (dichloromethane), CHCl3 (chloroform), MeOH (methanol), NH4OH (ammonium hydroxide), iPrOH (isopropyl alcohol).